Comparative effects of droloxifene, tamoxifen, and estrogen on bone, serum cholesterol, and uterine histology in the ovariectomized rat model

Ke, Hua Zhu; Chen, H.K.; Simmons, Hollis A.; Hua, Qi; Crawford, David T.; Pirie, C.M.; Chidsey-Frink, Kristin L.; Ma, Yang; Jee, Webster S. S.; Thompson, David D.

doi:10.1016/s8756-3282(96)00313-4

Cited by 115 publications

(70 citation statements)

References 40 publications

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“…In the present study, as expected, tamoxifen increased uterine weight, whereas letrozole reduced uterine weight relative to the controls. These effects of tamoxifen on the uterus and bone are consistent with previous reports (28,29,31). However, nude mice are immunodeficient, and others have shown that T-cell-deficient mice are protected against bone loss induced by ovariectomy (32).…”

Section: Discussionsupporting

confidence: 91%

Effects of the Antiestrogen Tamoxifen and the Aromatase Inhibitor Letrozole on Serum Hormones and Bone Characteristics in a Preclinical Tumor Model for Breast Cancer

Núñez¹,

Jelovac

Macedo

et al. 2004

Clinical Cancer Research

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Purpose: The purpose of this study was to evaluate and compare the effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on tumor growth, serum hormones, uterine weight, body composition, and bone characteristics in mice.Experimental Design: Human estrogen-dependent breast cancer cells stably transfected with the aromatase gene (MCF-7CA cells) were inoculated in Matrigel subcutaneously into ovariectomized nude mice. This model represents postmenopausal breast cancer in many respects, including the fact that estrogen is no longer produced by the ovaries and is not under feedback regulation by gonadotropins. Mice that received subcutaneously implanted MCF-7CA cancer cells were then treated with tamoxifen or letrozole for 7 weeks.Results: As reported previously, tumor growth was markedly inhibited by both tamoxifen (100 g/day) and letrozole (10 g/day). Tamoxifen treatment led to increased bone mineral density (BMD) and hyperplastic uteri. Mice treated with letrozole had significantly smaller uteri than the controls and tamoxifen-treated mice. Letrozole did not affect BMD. There was no significant difference in systemic leptin and insulin-like growth factor I levels as a result of tamoxifen or letrozole treatment. Conclusions:Tamoxifen treatment inhibited breast cancer cell growth and increased BMD but caused uterine hypertrophy in this preclinical model of postmenopausal breast cancer. Letrozole inhibited tumor growth without inducing uterine hypertrophy. In addition, letrozole had no effect on BMD. These findings provide experimental evidence that letrozole is an effective and safe (in terms of risk of endometrial cancer risk and osteoporosis) alternative or complement to tamoxifen treatment for breast cancer.

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Section: Discussionsupporting

confidence: 91%

Effects of the Antiestrogen Tamoxifen and the Aromatase Inhibitor Letrozole on Serum Hormones and Bone Characteristics in a Preclinical Tumor Model for Breast Cancer

Núñez¹,

Jelovac

Macedo

et al. 2004

Clinical Cancer Research

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“…Thus, the OVX rat is a sensitive model to evaluate uterine hypertrophy. The uterine weight decreased to a level of about 30% of sham control 4 weeks post-OVX in 4-month-old rats (19,20). As shown in Figure 7A, LAS at doses equal to or greater than 10 pg/kg/day slightly but significantly increased uterine wet weight with no dose-dependent response for up to 1000 pg/kg/day as compared with vehicle-treated OVX rats (27).…”

Section: Effects Of Ias On Uterine Tissue Of Female Ratsmentioning

confidence: 87%

“…A tissue selective estrogen receptor modulator without estrogenic activity in the breast and uterus would improve the negative side-effect profile of estrogen and overcome these compliance hurdles. A new class of agents, named selective estrogen receptor modulators (SERMs), has been investigated as an alternative to estrogen or hormone replacement therapy in preclincal and clinical studies (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). It has been reported that raloxifene, the first agent from this class approved for the prevention and treatment of postmenopausal osteoporosis, prevented bone loss, increased bone mineral density, reduced skeletal fracture, reduced risk of breast cancer, and decreased serum low-density lipoprotein cholesterol without uterine stimulating effects in postmenopausal women (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator, in preclinical studies

Brown

Thompson

2002

AGE

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Estrogen replacement therapy is reported to reduce the incidence of vertebral fractures in postmenopausal women, however, its compliance is limited because of side effects and safety concerns. Estrogen's side effects on breast and uterine tissues leading to the potential increased risk of uterine and breast cancer limit widespread estrogen usage. Thus, there is a significant medical need for a therapy that protects against postmenopausal bone loss but is free of estrogen's negative effects on reproductive tissues. Selective estrogen receptor modulators (SERMs) have been investigated as an alternative to hormone replacement therapy. One such compound, raloxifene, has been approved for the prevention and treatment of osteoporosis.Lasofoxifene (LAS), a new, nonsteroidal, and potent SERM, is an estrogen antagonist or agonist depending on the target tissue. LAS selectively binds with high affinity to human estrogen receptors. In ovariectomized (OVX) rat studies, LAS prevented the decrease in femoral bone mineral density, tibial and lumbar vertebral trabecular bone mass at an EDlo o of about 60 ~g/kg/day. LAS inhibited the activation of trabecular and endocortical bone resorption and bone turnover in tibial metaphyses and diaphyses, and lumbar vertebral body in OVX rats. In addition, LAS decreased total serum cholesterol, inhibited body weight gain and increased soleus muscle weight in OVX rats. Similarly, LAS prevented bone loss induced by orchidectomy or aging in male rats by decreasing bone resorption and bone turnover while it had no effect in the prostate. Further, LAS decreased total serum cholesterol in intact aged male rats or in orchidectomized male rats. Synergestic skeletal effects were found with LAS in combination with bone anabolic agents such as prostaglandin E 2 (PGE2), parathyroid hormone (PTH) or a growth hormone secretagoue (GHS) in OVX rats. In combination with estrogen, LAS inhibited the uterine stimulating effects of estrogen but did not block the bone protective effects of estrogen. In immature and aged female rats, LAS did not affect the uterine weight and uterine histology. In OVX adult female rats, LAS slightly but significantly increased uterine weight. These results demonstrated that LAS produced effects on the skeleton indistinguishable from estrogen in female and male rats. However, unlike estrogen, I_AS had little effect on uterine weight and cellular proliferation of uterus in female rats. In preclinical anti-tumor studies, LAS inhibited human breast cancer growth in mice bearing MCF7 tumors, prevented NMU-induced mammary carcinomas and possessed chemotherapeutic effects in NMU-induced carcinomas in rats.Therefore, we conclude that LAS possesses the antiestrogenic effects in breast tissue and estrogenic effects in bone and serum cholesterol, but lacks estrogen's side effects on uterine tissue. These data support the therapeutic potential of I_AS for the prevention and treatment of postmenopausal bone loss and mammary carcinomas in humans.

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“…All parameters were affected by exercise, especially mechanical bone strength, and the ash content of femur in OVX/Ex compared with SHAM/Cont showed its influence. Though various treatments such as hormone administration for prevention of bone loss have been performed 2,8,9) , it is considered that physical activity is the briefest prevention and treatment. Therefore the study of this field could be important.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Physical Activity on Bone in Ovariectomized Mice.

et al. 2000

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Abstract. The effects of physical activity, treadmill running, on bone of ovariectomized mice were investigated. Forty 12-week-old female ICR mice were used. They were ovariectomized (OVX) or shamoperated (SHAM) and half of them were run on a treadmill at 16 m/min, 5 days/week for 6 weeks (Ex). All animals were sacrificed at week 12 after operation. Mechanical strength of the left femur and tibia were measured by the three-point bending strength test. The bones were dried, weighed and burned to ash. Mechanical strength and ash content of the femur and tibia in Ex group were significantly higher than those of control animals. Also mechanical strength of femur and tibia in OVX/Ex were not different from SHAM/Cont mice. Physical activity, treadmill running, thus affected inhibition of bone loss and maintenance of bone mass. It is necessary to continue this basic study to determine effective modes of physical activity.

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Comparative effects of droloxifene, tamoxifen, and estrogen on bone, serum cholesterol, and uterine histology in the ovariectomized rat model

Cited by 115 publications

References 40 publications

Effects of the Antiestrogen Tamoxifen and the Aromatase Inhibitor Letrozole on Serum Hormones and Bone Characteristics in a Preclinical Tumor Model for Breast Cancer

Effects of the Antiestrogen Tamoxifen and the Aromatase Inhibitor Letrozole on Serum Hormones and Bone Characteristics in a Preclinical Tumor Model for Breast Cancer

Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator, in preclinical studies

Effect of the Physical Activity on Bone in Ovariectomized Mice.

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